title: Increased SRF transcriptional activity  in human and mouse skeletal muscle  is a signature of insulin resistance.
abstract: Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH(+)) of T2D; and family history-negative control individuals (FH(–)). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH(+) groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH(+) and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.
authors.affiliation: Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wanzhu
authors.initials: W
authors.lastname: Jin
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.forename: Tanner
authors.initials: T
authors.lastname: Boes
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Merve
authors.initials: M
authors.lastname: Emecan
authors.forename: Connor
authors.initials: C
authors.lastname: Fitzpatrick
authors.forename: Anish
authors.initials: A
authors.lastname: Sen
authors.forename: Ankit
authors.initials: A
authors.lastname: Shah
authors.forename: Edward
authors.initials: E
authors.lastname: Mun
authors.forename: Vokes
authors.initials: V
authors.lastname: Vokes
authors.forename: Joshua
authors.initials: J
authors.lastname: Schroeder
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tatro
authors.forename: Jose
authors.initials: J
authors.lastname: Jimenez-Chillaron
authors.forename: Mary-Elizabeth
authors.initials: ME
authors.lastname: Patti
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001706:Biopsy; D015331:Cohort Studies; D003599:Cytoskeleton / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000199:Actins; D007328:Insulin; D026362:Serum Response Factor; D005947:Glucose